Clomiphene citrate (CC) is a selective estrogen receptor modulator (SERM) that increases pituitary production of gonadotropins by inhibiting the estrogen receptor negative feedback on the hypothalamus and the pituitary gland. The drug was created for use in women to treat oligomenorrhea and later expanded to treat anovulation as a fertility aid. CC is not an anabolic steroid. CC is chemically a mixture of two geometric isomers, enclomiphene and zuclomiphene, and is a synthetic estrogen with both agonist/antagonist properties. Zuclomiphene is the more active isomer and stays bound for longer periods of time giving Clomiphene a half-life of 24 hours.

In men, CC can block the binding of estrogen with its corresponding receptors in the hypothalamus, which results in the hypothalamus continuing to secrete gonadotropin-releasing hormone (GnRH), also known as luteinizing-hormone-releasing hormone and luliberin. GnRH is a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. While FSH stimulates spermatogenesis in the Sertoli cells of the testes, our primary focus will be the effect of LH on the Leydig cells of the testes to increase (endogenous) production of testosterone. Maintaining this endogenous production of testosterone counteracts some of the unwanted side effects of providing men with an external source of testosterone through HRT.

As the male body produces more testosterone, the enzyme 5a-aromatase converts (aromatizes) the testosterone into estradiol, which ordinarily acts on the pituitary gland to decrease production of LH and on the hypothalamus to produce less GnRH. As depicted by the solid lines crossing the negative pathways in [Figure 1], CC can be used clinically in men to block this negative feedback of estradiol on the hypothalamic-pituitary-testes axis (HPTX) and maintain endogenous testosterone production.

In the absence of a SERM such as CC, men who receive testosterone replacement therapy will generally find their endogenous testosterone production declines proportionally with the dose of external testosterone received. Their bodies come to rely on the external source of testosterone and significantly reduce internal production of the hormone. This down-regulation of the HPTX, inter alia, leads to a physiological manifestation of testicular shrinkage, but other non-visible consequences of HPTX atrophy have yet to be fully explored. If the HRT ceases, the testes would need time to return to pre-treatment size and pre-treatment levels of production of testosterone due to a prolonged period of inactivity.

Although primary care physicians profess to understand HRT for men, the fact that less than 1% of these physicians prescribe CC to their male patients on HRT demonstrates a gap in knowledge about best clinical practices. This article is intended to provide physicians with guidance on the safe and effective use of CC in men as part of HRT. A prior draft of this article, with its accompanying references, has already led one of the Blue Cross Blue Shield payers in the USA to cover and reimburse men for CC, and hopefully that payer reimbursement trend will continue. Because CC's mechanism of action works to inhibit the negative feedback loop of estradiol, rather than directly stimulating production of testosterone, it is not surprising that CC as monotherapy will generally fail to raise serum testosterone to the optimal range for men experiencing the effects of andropause.

Published Clinical Evidence and Intended Uses in Men

Published clinical studies involving the administration of CC to men date back at least to 1973.[1] The studies reported CC administration at doses as high as 100 mg/day were safe for the period studied.[2],[3],[4],[5],[6],[7] Although CC doses as high as 100 mg/day were published in the literature, the most common dose in clinical studies was 50 mg/day, particularly for those studies lasting several months up to one year. [8],[9],[10],[11],[12],[13] The published literature on CC use in men primarily focused on treatment for male infertility; however, the literature contained no mention that obstetrician-gynecologists attempting to help their female patients become pregnant had been prescribing CC off-label to the husbands or male partners of their female patients to increase the chances of conception. Thus, by the time our case study commenced in 2010, the obstetrician-gynecologist and reproductive endocrinologist professions had several decades of real world evidence on the safety of CC use in male partners of female patients. But couples normally seek assistance with conception for a limited period of months or even a couple of years, not the extended 30-40 year period proposed for HRT in post-andropausal men. In order to obtain more information on the multi-year safety profile of CC in men, it was necessary to look beyond the published medical literature.

Renew Man Observational Data

Renew Man, Inc., is a private firm in the USA that offers HRT to its male customers. At the time that our case study investigation of male HRT began in 2009, a technical specialist with Renew Man shared some of the key findings from the company's then 10-year history of patient use of various forms of HRT including CC. The database comprised approximately 500 men, and most of the patients remained enrolled throughout the observation period. Renew Man considers its observational data to be proprietary and does not intend to publish the results in a medical journal, because the data gives the firm a competitive advantage vis-à-vis other firms offering HRT. Nevertheless, as of 2010, the medical literature had only limited duration studies usually of less than a year for men taking CC. Consequently, the Renew Man perspective on both long-term safety and efficacy of CC in men filled an important gap.

The key findings from the Renew Man observational data were that (1) CC as monotherapy was unlikely to achieve optimal serum testosterone levels as men progressed through andropause; and (2) none of the patients reported serious side effects from CC, and the unwanted minor side effects, e.g., blurred vision or headaches, were reversed when the CC therapy was temporarily stopped.

Large doses of Clomiphene could enlarge the pituitary gland, which is located near the optic nerve. If the pituitary swells too much, some Clomiphene users have reported blurred vision. Temporarily discontinuing Clomiphene use normally reverses the blurred vision. The listed possible side effects for Clomiphene include hot flashes, nausea, dizziness, headaches, and temporarily blurred vision. Such side effects appear more frequently in women, however, as they feel the effects of estrogen manipulation much more readily than men.

CC was shown to increase both endogenous testosterone production and fertility among the male patients included in the observational tracking. The doses reflected in the Renew Man observational data ranged from 10 mg to 50 mg CC daily.

Aside from its findings on the safety and efficacy of various forms of HRT in men, Renew Man provided a valuable service to the public by describing the caution a male patient must exercise in selecting a physician to prescribe HRT initially and monitor his progress throughout the course of treatment. According to Renew Man, because of relatively lax medical laws and regulations in the state of Florida in the United States, many subpar providers of HRT operate out of that state. Among the many errors committed by these subpar providers were using the same HRT protocol for all patients, rather than an individualized approach; failing to test thyroid hormone and dehydroepiandrosterone (DHEA) levels; failing to monitor and control hematocrit thereby increasing the risk of stroke some men experience from taking therapeutic doses of testosterone; inconsistent or even nonexistent follow-up biometric testing; and “stacking hormones,” which is the use of several synthetic versions of testosterone rather than a bioidentical hormone product, such as (generic) compounded testosterone.[14]

Family doctors “though well intentioned,” have woefully inadequate training to begin HRT for male patients. They frequently will attempt to boost testosterone with a synthetic FDA-approved prescription drug without realizing that any increase in testosterone will alter the male patient's entire hormone cascade. It never dawns on many of these providers that they need to check and prescribe drugs to control the patient's estradiol, dihydrotestosterone, and even thyroid hormone levels. According to Renew Man, the errors committed by inadequately trained family medicine practitioners include incorrect initial diagnosis, e.g., treating depression and lethargy with an antidepressant rather than recognizing it as a symptom of the larger andropause condition; treating all male patients with the exact same protocol; failing to periodically retest estradiol – which is known to cause myocardial infarctions, prostate cancer, and gynocomastia when elevated in men; failing to test for DHEA and thyroid hormones compounded by failure to recognize low-normal readings on Free T3 reflect hypothyroidism, another medical condition often present with andropause; and inconsistent or nonexistent biometric testing of male patients on HRT.[14]

“Urologists often have the knowledge base necessary to treat andropause, but will not take the time to provide safe, quality treatment. Urologists are often high-production doctors, and their practices see a high volume of patients. Hormone replacement therapy and treatment (if done correctly) takes time, patience, and follow-up.”[14] An award-winning, board certified urologist in Tennessee advised me that he was unfamiliar with and uncomfortable prescribing CC and bioidentical testosterone needed in male HRT.

As to endocrinologists, “hormones are their specialty. However, 90+% of their clients are usually women and diabetics. Endocrinologists may know a lot about hormones, but they treat few if any andropausal men, and surprisingly, they usually lack the knowledge to do so effectively.”[14] My own research confirms these statements from Renew Man. An endocrinologist affiliated with a medical research foundation told me that male patients seeking HRT would be better served with a primary care physician who took the time to learn about male HRT through continuing medical education, rather than the typical endocrinologist. In addition, a board-certified endocrinologist in East Tennessee gave me a list of blood tests he would order for a male patient on HRT, but he failed to check for serum dihydrotestosterone (DHT) levels - an obvious error.

Methods

Our case study reflects a five-year study of a 47-year old man seeking treatment for andropause. Baseline levels for total testosterone (TT), free testosterone (FT), estradiol, DHT, LH, and prostate specific antigen (PSA) were measured and recorded at the outset of the HRT. The patient commenced HRT using compounded testosterone cream (CTC) 100 mg applied topically each day. The topically applied CTC was fully absorbed within two hours. Target levels for TT and FT were achieved. After one year on HRT, the patient observed evidence of HPTX down-regulation confirmed by low-normal serum LH levels. The patient was then taken off CTC and given CC 50 mg/day to test the efficacy of CC as monotherapy. The target level range for TT was 750-900 ng/dL and FT was 20-25 pg/mL. As shown in [Figure 2], the optimal ranges were based on the testosterone level that a typical male 20-year old would produce.

On CC monotherapy, the patient achieved only 66% of target for TT and less than 66% for FT. Taking 50 mg/day of CC together with 100 mg/day of CTC proved to be too high a dose of T, as serum TT and FT generally exceeded the targeted levels.

After trying various combinations and allowing the body time to adjust to adjuvant therapy, the patient was stabilized to reach target levels for TT and FT on a dose of 25 mg/day CC together with 100 mg/day of CTC. Average post-treatment TT levels were 538 ng/dL in the CC monotherapy portion of the study, and 982 ng/dL when CC was used as adjuvant therapy to HRT. Average post-treatment FT levels were 14.7 pg/mL in the CC monotherapy portion of the study and 22.0 pg/mL in the adjuvant CC portion. CC consumption raised serum luteinizing hormone levels from the lowest quartile with HRT to the mid-point and third quartile of the reference range [1.7, 8.6] mIU/mL.

Beginning in 2013 and continuing to present, the patient experienced more therapeutic benefit from TT levels above the original target of 750-900 ng/dL. Consequently, the targeted TT level was raised to 1,000-1,200 ng/dL, while maintaining estradiol in the range of 20-30 pg/mL and DHT in the range of 30-50 ng/dL. In the absence of CC, the patient's LH levels typically registered in the lowest quartile of the normal range and even dropped slightly below the normal range on one blood test. A 25 mg/day dose of CC led to adequate up-regulation of the HPTX to maintain serum LH at or above the targeted midpoint of the reference range.

Beginning in 2014, the patient switched from CTC to compounded testosterone troches (CTT) placed in either the buccal cavity of the mouth or sublingual. Testosterone from troches is fully absorbed as soon as the troche has dissolved, which is usually within one minute. The case study patient's blood was tested approximately four minutes after consumption of the troche, and TT had reached the 1,200 ng/ dL targeted peak. In order to spread out absorption, the troche can be removed after 30 seconds and then reinserted later that day, e.g. immediately prior to an exercise workout.

A 100 mg/day dose of topically applied CTC is roughly equivalent to a 10 mg/day dose of CTT, and the patient continued with 25 mg/day CC during the first seven months of this year. However, beginning in July 2014, the patient switched to CTT supplied by the Life Extension Pharmacy and experienced novel results. First, the patient overshot the 1,000-1,200 ng/dL targeted TT level on three separate blood tests over six weeks and was taken off the CC dose. Second, the patient has maintained LH levels above the mid-point of the [1.7, 8.6] mIU/mL range even without a SERM to up-regulate the HPTX. It is not clear whether some biochemical properties of the CTT or the prolonged use of CC have achieved this result.

Discussion & Conclusion

Considerable evidence has emerged that the bioidentical hormones used by compounding pharmacies are better than the synthetic hormones,[15],[16],[17],[18],[19] which are patented and sold at comparatively high prices by the pharmaceutical industry. The payers frequently refuse to consider real world evidence on the efficacy of compounded hormone products, just as they have been reluctant to expand coverage to include CC use by men. As a result, male patients in andropause are forced to pay for CC out-of-pocket and seek low-cost sources of supply.

Throughout the five-year period 2010 – 2014 (inclusive) of this case study, the Indian pharmaceutical company Cipla Global Limited has consistently been the worldwide low-price leading supplier of CC. Online pharmacies offer generic CC 100 mg tablets for quantity 120 at a price of $118 USD. That price equates roughly to $1/pill and $0.25 for the 25 mg daily dose, or $7.50/month. The 50 mg tablets, with quantity 120, can be purchased for $100 USD from online pharmacies. Because Clomiphene is a generic drug, neither Cipla nor any other generic drug manufacturer has a profit incentive to seek regulatory approval for a new indication for Clomiphene's use in men.

However by the last quarter of 2014, American pharmaceutical firm Repros Therapeutics, Inc., expects to complete Phase 3 clinical trials in the USA for a pipeline drug that is the (less active) isomer enclomiphene, for use in men.[20],[21] Yet generic Clomiphene remains a highly effective alternative and presently costs just $7.50/month for adjuvant therapy dosing of 25 mg/day.

Male patients in andropause who obtain HRT treatment will generally find that endogenous production of testosterone declines significantly with down-regulation of the HPTX. The long-term (40-year) consequences for allowing the HPTX to atrophy have yet to be determined. CC as adjuvant therapy with HRT successfully restores internal testosterone production. The dose for CC will vary by patient based on the degree of atrophy, but a reasonable starting dose would be 25 mg/day CC for aging male patients on HRT for andropause. Although CC is intended and known to block the estrogen receptors on the hypothalamus and pituitary gland, it remains an issue for further research to identify adverse consequences, if any, for the unintended blockade of estrogen receptors in other parts of the body. As shown in the following figure adapted from Gustafsson (1999),[22] the male (and female) body contains estrogen receptors α (ERα) and estrogen receptors β (ERβ3) throughout.

[Figure 3] shows the presence of two distinct estrogen receptors, ERα and ERβ, in the breast tissue, cardiovascular system, and in bones. The latter location in the skeletal structure is of particular concern for male andropause patients, because estrogen is required for bone mineralization and to prevent osteopenia and osteoporosis, another disease of aging that frequently begins onset concomitantly with andropause. However, two Yale University medical researchers discovered that CC increased bone mass density in women, which they patented as a predictor of fertility.[23] If CC similarly resulted in denser bone masses in men, then CC therapy could offer prophylaxis against osteopenia and osteoporosis.

Both ERα and ERβ bind estrogen as well as other agonists and antagonists, but the two receptors have distinctly different localizations and concentrations within the body. For example, the liver has ERα, while the GI tract has ERβ. Structural differences between ERα and ERβ permit a multitude of diverse and complex processes, which from a pharmacovigilance perspective requires further safety studies for the long-term consequences of ER-blockade by CC in men.